tbuckley/cabot-search huggingface dataset:
Reversing the PAI-1-induced fibrotic immune exclusion of solid tumor by multivalent CXCR4 antagonistic nano-permeator
Authors: Jingwen Dong, Chenfei Zhu, Ying Huang, Quanhao Li, Jing Li, Zheng Wang, Yixin Wang, Zhanwei Zhou, Minjie Sun
Journal: Acta Pharmaceutica Sinica B (2022)

Fibrosis is one of the key factors that lead to the immune exclusion of solid tumors. Although degradation of fiber is a promising strategy, its application was still bottlenecked by the side effects of causing metastasis, resulting in the failure of immunotherapy. Here, we developed an antimetastatic polymer (HPA) for the delivery of chemo-drug and antifibrotic siPAI-1 to form the nano-permeator. Nano-permeator shrank after protonation and deeply penetrated into the tumor core to down-regulate the expression of PAI-1 for antifibrosis, and further promoted the sustained infiltration and activation of T cells for killing tumor cells. Moreover, metastasis after fiber elimination was prevented by multivalent CXCR4 antagonistic HPA to reduce the attraction of CXCL12 secreted by distant organs. The administration of stroma-alleviated immunotherapy increased the infiltration of CD8+ T cells to 52.5% in tumor tissues, inhibiting nearly 90% metastasis by HPA in distant organs. The nano-permeator reveals the mechanism and correlation between antifibrosis and antimetastasis and was believed to be the optimizing immunotherapy for solid fibrotic tumors.
CircPDIA4 Induces Gastric Cancer Progression by Promoting ERK1/2 Activation and Enhancing Biogenesis of Oncogenic circRNAs
Authors: Yue Shen, Nasha Zhang, Jie Chai, Teng Wang, Chi Ma, Linyu Han, Ming Yang
Journal: Cancer Research (2022)

Abstract Circular RNAs (circRNA) are a group of noncoding, covalently uninterrupted loop transcripts, most of which remain to be functionally characterized. Here, we identified circPDIA4 as an oncogenic circRNA in gastric cancer. Clinically, circPDIA4 was significantly upregulated in malignant tissues and was associated with poor survival of patients with gastric cancer. The biogenesis of circPDIA4 was mediated by the RNA-binding protein Quaking, which bound introns 2 and 4 of PDIA4 pre-mRNA to promote backsplicing of exons 3 and 4. Elevated expression of circPDIA4 promoted distant metastasis in various mouse xenograft models in vivo and accelerated cancer cell invasion in vitro. CircPDIA4 functioned through distinct oncogenic mechanisms in the cytoplasm and the nucleus. Cytoplasmic circPDIA4 bound to ERK1/2 and sustained hyperactivation of the MAPK pathway by preventing DUSP6-mediated ERK1/2 dephosphorylation. Notably, circPDIA4 depletion enhanced the sensitivity of gastric cancer cells to ERK inhibitors. In the nucleus, circPDIA4 interacted with DHX9 as a decoy and repressed its inhibitory functions on circRNA biogenesis to boost expression of multiple oncogenic circRNAs, which promoted gastric cancer progression. These findings reveal a dual tumor-promoting mechanism for circPDIA4 by regulating oncogenic circRNA biogenesis and increasing MAPK activity. CircPDIA4 should be investigated further as a potential prognostic biomarker and therapeutic target in gastric cancer. Significance: Quaking-regulated circPDIA4 mediates different mechanisms in the nucleus and cytoplasm that coordinate to promote progression and drug resistance in gastric cancer.
Exploiting the immunogenic potential of standard of care radiation or cisplatin therapy in preclinical models of HPV-associated malignancies
Authors: Joshua T Kowalczyk, Kellsye P Fabian, Michelle R Padget, Diana C Lopez, Austin TK Hoke, Clint T Allen, Mario Hermsen, Nyall R London,, James W Hodge
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background While radiation and chemotherapy are primarily purposed for their cytotoxic effects, a growing body of preclinical and clinical evidence demonstrates an immunogenic potential for these standard therapies. Accordingly, we sought to characterize the immunogenic potential of radiation and cisplatin in human tumor models of HPV-associated malignancies. These studies may inform rational combination immuno-oncology (IO) strategies to be employed in the clinic on the backbone of standard of care, and in so doing exploit the immunogenic potential of standard of care to improve durable responses in HPV-associated malignancies. Methods Retroviral transduction with HPV16 E7 established a novel HPV-associated sinonasal squamous cell carcinoma (SNSCC) cell line. Three established HPV16-positive cell lines were also studied (cervical carcinoma and head and neck squamous cell carcinoma). Following determination of sensitivities to standard therapies using MTT assays, flow cytometry was used to characterize induction of immunogenic cell stress following sublethal exposure to radiation or cisplatin, and the functional consequence of this induction was determined using impedance-based real time cell analysis cytotoxicity assays employing HPV16 E7-specific cytotoxic lymphocytes (CTLs) with or without N803 (IL-15/IL-15-Rα superagonist) or exogenous death receptor ligands. In vitro observations were translated using an in vivo xenograft NSG mouse model of human cervical carcinoma evaluating cisplatin in combination with CTL adoptive cell transfer. Results We showed that subpopulations surviving clinically relevant doses of radiation or cisplatin therapy were more susceptible to CTL-mediated lysis in four of four tumor models of HPV-associated malignancies, serving as a model for HPV therapeutic vaccine or T-cell receptor adoptive cell transfer. This increased killing was further amplified by IL-15 agonism employing N803. We further characterized that radiation or cisplatin induced immunogenic cell stress in three of three cell lines, and consequently demonstrated that upregulated surface expression of Fas and TRAIL-R2 death receptors at least in part mediated enhanced CTL-mediated lysis. In vivo, cisplatin-induced immunogenic cell stress synergistically potentiated CTL-mediated tumor control in a human model of HPV-associated malignancy. Conclusion Standard of care radiation or cisplatin therapy induced immunogenic cell stress in preclinical models of HPV-associated malignancies, presenting an opportunity poised for exploitation by employing IO strategies in combination with standard of care.
Intratumoral oncolytic virus V937 plus ipilimumab in patients with advanced melanoma: the phase 1b MITCI study
Authors: Brendan D Curti, Jon Richards, John R Hyngstrom, Gregory A Daniels, Mark Faries, Lynn Feun, Kim A Margolin, Sigrun Hallmeyer, Mark Grose, Yiwei Zhang, Anlong Li, Robert H I Andtbacka
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Intratumoral administration of V937, a bioselected, genetically unmodified coxsackievirus A21, has previously demonstrated antitumor activity in patients with advanced melanoma as monotherapy and in combination with the programmed cell death 1 (PD-1) antibody pembrolizumab. We report results from an open-label, single-arm, phase 1b study ( NCT02307149 ) evaluating V937 plus the cytotoxic T-lymphocyte antigen 4 inhibitor ipilimumab in patients with advanced melanoma. Methods Adult patients (aged ≥18 years) with histologically confirmed metastatic or unresectable stage IIIB/C or IV melanoma received intratumoral V937 on days 1, 3, 5, 8, and 22 and every 3 weeks (Q3W) thereafter for up to 19 sets of injections plus intravenous ipilimumab 3 mg/kg Q3W administered for four doses starting on day 22. Imaging was performed at screening, on days 43 and 106 and every 6 weeks thereafter; response was assessed by immune-related response criteria per investigator assessment. Primary endpoints were safety in all treated patients and objective response rate (ORR) in all treated patients and in patients with disease that progressed on prior anti-PD-1 therapy. Results Fifty patients were enrolled and treated. ORR was 30% (95% CI 18% to 45%) among all treated patients, 47% (95% CI 23% to 72%) among patients who had not received prior anti-PD-1 therapy, and 21% (95% CI 9% to 39%) among patients who had experienced disease progression on prior anti-PD-1 therapy. Tumor regression occurred in injected and non-injected lesions. Median immune-related progression-free survival was 6.2 months (95% CI 3.5 to 9.0 months), and median overall survival was 45.1 months (95% CI 28.3 months to not reached). The most common treatment-related adverse events (AEs) were pruritus (n=25, 50%), fatigue (n=22, 44%), and diarrhea (n=16, 32%). There were no V937-related dose-limiting toxicities and no treatment-related grade 5 AEs. Treatment-related grade 3 or 4 AEs, all of which were considered related to ipilimumab, occurred in 14% of patients (most commonly dehydration, diarrhea, and hepatotoxicity in 4% each). Conclusions Responses associated with intratumoral V937 plus ipilimumab were robust, including in the subgroup of patients who had experienced disease progression on prior anti-PD-1 therapy. Toxicities were manageable and consistent with those of the individual monotherapies.
PP4 inhibition sensitizes ovarian cancer to NK cell-mediated cytotoxicity via STAT1 activation and inflammatory signaling
Authors: Remya Raja, Christopher Wu, Esen Yonca Bassoy, Thomas E Rubino, Emma C Utagawa, Paul M Magtibay, Kristina A Butler, Marion Curtis
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Increased infiltration of T cells into ovarian tumors has been repeatedly shown to be predictive of enhanced patient survival. However, despite the evidence of an active immune response in ovarian cancer (OC), the frequency of responses to immune checkpoint blockade (ICB) therapy in OC is much lower than other cancer types. Recent studies have highlighted that deficiencies in the DNA damage response (DDR) can drive increased genomic instability and tumor immunogenicity, which leads to enhanced responses to ICB. Protein phosphatase 4 (PP4) is a critical regulator of the DDR; however, its potential role in antitumor immunity is currently unknown. Results Our results show that the PP4 inhibitor, fostriecin, combined with carboplatin leads to increased carboplatin sensitivity, DNA damage, and micronuclei formation. Using multiple OC cell lines, we show that PP4 inhibition or PPP4C knockdown combined with carboplatin triggers inflammatory signaling via Nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 1 (STAT1) activation. This resulted in increased expression of the pro-inflammatory cytokines and chemokines: CCL5 , CXCL10 , and IL-6 . In addition, IFNB1 expression was increased suggesting activation of the type I interferon response. Conditioned media from OC cells treated with the combination of PP4 inhibitor and carboplatin significantly increased migration of both CD8 T cell and natural killer (NK) cells over carboplatin treatment alone. Knockdown of stimulator of interferon genes (STING) in OC cells significantly abrogated the increase in CD8 T-cell migration induced by PP4 inhibition. Co-culture of NK-92 cells and OC cells with PPP4C or PPP4R3B knockdown resulted in strong induction of NK cell interferon-γ, increased degranulation, and increased NK cell-mediated cytotoxicity against OC cells. Stable knockdown of PP4C in a syngeneic, immunocompetent mouse model of OC resulted in significantly reduced tumor growth in vivo . Tumors with PP4C knockdown had increased infiltration of NK cells, NK T cells, and CD4 + T cells. Addition of low dose carboplatin treatment led to increased CD8 + T-cell infiltration in PP4C knockdown tumors as compared with the untreated PP4C knockdown tumors. Conclusions Our work has identified a role for PP4 inhibition in promoting inflammatory signaling and enhanced immune cell effector function. These findings support the further investigation of PP4 inhibitors to enhance chemo-immunotherapy for OC treatment.
More treatment options for rifampicin-resistant tuberculosis: the role of economic evaluation in informing uptake
Authors: Sedona Sweeney, Maninder Pal Singh
Journal: The Lancet Global Health (2022)

There have been substantial advances in treatment options for multidrug-resistant and rifampicin-resistant tuberculosis. Just a few years ago, a typical patient faced months of painful injections, life-changing adverse effects, and a very small chance of cure. This year, WHO announced forthcoming updates to global guidelines including 6-month and 9-month all-oral regimens for treatment of multidrug-resistant and rifampicin-resistant tuberculosis.1 In the context of these rapidly changing options for treating multidrug-resistant and rifampicin-resistant tuberculosis and persisting high costs of newer drugs such as bedaquiline, countries are facing difficult decisions about when and how to incorporate new drug regimens into national guidelines, and the economic effects of new regimens will be a key consideration in their uptake.
Global state of education-related inequality in COVID-19 vaccine coverage, structural barriers, vaccine hesitancy, and vaccine refusal: findings from the Global COVID-19 Trends and Impact Survey
Authors: Nicole Bergen, Katherine Kirkby, Cecilia Vidal Fuertes, Anne Schlotheuber, Lisa Menning, Stephen Mac Feely, Katherine O'Brien, Ahmad Reza Hosseinpoor
Journal: The Lancet Global Health (2022)
Diagnostic capacity for invasive fungal infections in advanced HIV disease in Africa: a continent-wide survey
Authors: Sulaiman Lakoh, Pocha Samuel Kamudumuli, Richard O S Penney, Samson M Haumba, Joseph N Jarvis, Asha Jama Hassan, Ngando Laure E Moudoute, Bright K Ocansey, Santiago Izco, Stephen Kipkerich, Jahit Sacarlal, Abimbola T Awopeju, Nelesh P Govender, Cleophas If Malaba Munyanji, Kamwiziku Guyguy, Emma Orefuwa, David W Denning
Journal: The Lancet Infectious Diseases (2022)
3D‐Printed Centrifugal Pump Driven by Magnetic Force in Applications for Microfluidics in Biological Analysis (Adv. Healthcare Mater. 24/2022)
Authors: Byeongwook Jo, Yuya Morimoto, Shoji Takeuchi
Journal: Advanced Healthcare Materials (2022)

Dynamic Cell Cultures Article 2200593 by Shoji Takeuchi and co-workers proposes a 3D-printed centrifugal pump driven by magnetic force. Precise control of the flow rate and a wide range and variety of flow profiles are achieved by controlling the rotational speed of the motor. Compact size enables simple setups within commercially available culture dishes and tubes. Moreover, demonstrations of laminar flow production and perfusion culture are presented for biological applications in microfluidic devices.
Cost-effectiveness of Compression Therapy With Early Endovenous Ablation in Venous Ulceration for a Medicare Population
Authors: Hanke Zheng, Gregory A. Magee, Tze-Woei Tan, David G. Armstrong, William V. Padula
Journal: JAMA Network Open (2022)

Importance Venous leg ulcers (VLU) are the most common cause of lower extremity ulceration that commonly occur among older individuals and are characterized by a slow healing trajectory and frequent recurrence; in the United States, VLUs affect more than 600 000 people per year with an estimated cost of $3.5 billion. Clinical trial data show that early intervention with endovenous ablation substantially improves the healing rate and reduces recurrence among patients with VLUs, but there is a need to assess the cost-effectiveness of early endovenous ablation in the US context. Objectives To evaluate the cost-effectiveness of early endovenous ablation of superficial venous reflux in patients with VLU from the US Medicare perspective. Design, Setting, and Participants This economic evaluation used a Markov model to simulate the disease progression of VLU for patients receiving compression therapy with early vs deferred ablation over 3 years. The simulated cohort included patients with VLU aged 65 years and older who had clinical characteristics similar to those in the randomized Early Venous Reflux Ablation trial in the United Kingdom. Data were analyzed from September 2021 to June 2022. Main Outcomes and Measures Direct medical costs, quality-adjusted life years (QALYs), and the incremental monetary benefits at a willingness-to-pay threshold of $100 000/QALY. Univariate and probabilistic sensitivity analyses were performed to test uncertainty of model results. Results This model used a simulated cohort of patients with VLU aged 65 years and older enrolled in Medicare. Early ablation dominated, with a lower per-patient cost of $12 527 and an increase of 2.011 QALYs, whereas compression therapy with deferred ablation yielded a per-patient cost of $15 208 and 1.985 QALYs gained. At a $100 000/QALY cost-effectiveness threshold, the incremental net monetary benefit was $5226 per patient in favor of early ablation. Probability of healing, followed by the probability of recurrence, was the parameter with greatest impact on model uncertainty. The probabilistic sensitivity analysis showed that early ablation was cost-effective in 59.2% of simulations at the $100 000/QALY threshold. Conclusions and Relevance In this economic evaluation of compression therapy with early endovenous ablation, early intervention was dominant, as it was cost saving and generated greater QALYs over 3 years from the US Medicare perspective. Payers should prioritize coverage for early ablation to prevent VLU complications rather than treat a costly outcome that also reduces patient well-being.
Health system readiness and the implementation of rectal artesunate for severe malaria in sub-Saharan Africa: an analysis of real-world costs and constraints
Authors: Mark J Lambiris, Guy Ndongala Venga, Richard Ssempala, Victor Balogun, Katya Galactionova, Michael Musiitwa, Fred Kagwire, Oluseyi Olosunde, Emmanel Emedo, Sylvie Luketa, Moulaye Sangare, Valentina Buj, Giulia Delvento, Antoinette Tshefu, Jean Okitawutshu, Elizabeth Omoluabi, Phyllis Awor, Aita Signorell, Manuel W Hetzel, Tristan T Lee, Nina C Brunner, Nadja Cereghetti, Theodoor Visser, Harriet G Napier, Christian Burri, Christian Lengeler
Journal: The Lancet Global Health (2022)
Racial and Ethnic Disparities in Access to Minimally Invasive Mitral Valve Surgery
Authors: Laurent G. Glance, Karen E. Joynt Maddox, Michael Mazzefi, Peter W. Knight, Michael P. Eaton, Changyong Feng, Miklos D. Kertai, James Albernathy, Isaac Y. Wu, Julie A. Wyrobek, Marisa Cevasco, Nimesh Desai, Andrew W. Dick
Journal: JAMA Network Open (2022)

Importance Whether people from racial and ethnic minority groups experience disparities in access to minimally invasive mitral valve surgery (MIMVS) is not known. Objective To investigate racial and ethnic disparities in the utilization of MIMVS. Design, Setting, and Participants This cross-sectional study used data from the Society of Thoracic Surgeons Database for patients who underwent mitral valve surgery between 2014 and 2019. Statistical analysis was performed from January 24 to August 11, 2022. Exposures Patients were categorized as non-Hispanic White, non-Hispanic Black, and Hispanic individuals. Main Outcomes and Measures The association between MIMVS (vs full sternotomy) and race and ethnicity were evaluated using logistic regression. Results Among the 103 753 patients undergoing mitral valve surgery (mean [SD] age, 62 [13] years; 47 886 female individuals [46.2%]), 10 404 (10.0%) were non-Hispanic Black individuals, 89 013 (85.8%) were non-Hispanic White individuals, and 4336 (4.2%) were Hispanic individuals. Non-Hispanic Black individuals were more likely to have Medicaid insurance (odds ratio [OR], 2.21; 95% CI, 1.64-2.98; P &amp;amp;lt; .001) and to receive care from a low-volume surgeon (OR, 4.45; 95% CI, 4.01-4.93; P &amp;amp;lt; .001) compared with non-Hispanic White individuals. Non-Hispanic Black individuals were less likely to undergo MIMVS (OR, 0.65; 95% CI, 0.58-0.73; P &amp;amp;lt; .001), whereas Hispanic individuals were not less likely to undergo MIMVS compared with non-Hispanic White individuals (OR, 1.08; 95% CI, 0.67-1.75; P = .74). Patients with commercial insurance had 2.35-fold higher odds of undergoing MIMVS (OR, 2.35; 95% CI, 2.06-2.68; P &amp;amp;lt; .001) than those with Medicaid insurance. Patients operated by very-high volume surgeons (300 or more cases) had 20.7-fold higher odds (OR, 20.70; 95% CI, 12.7-33.9; P &amp;amp;lt; .001) of undergoing MIMVS compared with patients treated by low-volume surgeons (less than 20 cases). After adjusting for patient risk, non-Hispanic Black individuals were still less likely to undergo MIMVS (adjusted OR [aOR], 0.88; 95% CI, 0.78-0.99; P = .04) and were more likely to die or experience a major complication (aOR, 1.25; 95% CI, 1.16-1.35; P &amp;amp;lt; .001) compared with non-Hispanic White individuals. Conclusions and Relevance In this cross-sectional study, non-Hispanic Black patients were less likely to undergo MIMVS and more likely to die or experience a major complication than non-Hispanic White patients. These findings suggest that efforts to reduce inequity in cardiovascular medicine may need to include increasing access to private insurance and high-volume surgeons.
Diagnosis of histiocytic sarcoma by bone marrow aspiration
Authors: Jean‐Baptiste Rieu, Alban Canali, François Vergez, Barbara J. Bain
Journal: American Journal of Hematology (2022)

An 86-year-old man presented with asthenia and loss of appetite for 10 days. On examination, right inguinal lymphadenopathy was suspected. Computed tomography confirmed this observation and, in addition, showed mediastinal and retroperitoneal lymphadenopathy. The blood count showed pancytopenia (hemoglobin concentration 77 g/L, platelet count 19 × 109/L, neutrophils 0.5 × 109/L). No abnormal cells were observed in the blood film. A bone marrow aspirate showed 75% large pleomorphic immature neoplastic cells (images, May-Grünwald-Giemsa, ×100 objective) with irregular nuclei and abundant blue-gray cytoplasm. Phagocytosis was often observed (upper right and lower images). Some of the neoplastic cells had long cytoplasmic tails (upper images) or prominent cytoplasmic protrusions (lower left). Flow cytometric immunophenotyping showed expression of myeloid markers, CD13 and CD33, but no expression of myeloperoxidase, CD117, CD34, CD11b, CD14, CD64 or lymphoid markers, CD19, CD79a and cytoplasmic CD3. These cells were positive for CD4 and HLA-DR. On cytogenetic analysis the karyotype was 44,X,−Y,add(1)(p36),der(8;15)(q10;q10),add(11)(q13),−13,add(16)(p13),add(20)(q13)[21]. Molecular analysis (next-generation sequencing and reverse transcriptase multiplex ligation-dependent probe amplification) revealed no mutation. The presence of neoplastic cells with long cytoplasmic tails suggested the possibility of plasmacytoid dendritic cell neoplasm while the prominent phagocytosis strongly favored a histiocytic neoplasm. Immunohistochemistry of the inguinal lymph node biopsy showed infiltration by neoplastic cells which expressed histiocytic markers, CD68 and CD163, with no expression of langerin (CD207) or plasmacytoid dendritic cells-associated antigens (CD123 and CD303). These results were indicative of histiocytic sarcoma with bone marrow involvement. Palliative chemotherapy was proposed but the patient died a few days later. Diagnosis of histiocytic sarcoma on bone marrow aspiration is a rare and challenging situation. Morphological features of neoplastic cells, much closer to tissue histiocytes than monoblasts, promonocytes, and monocytes, are of considerable importance and should help to distinguish histiocytic sarcoma from acute monoblastic/monocytic leukemia. Spindle-shaped cells are sometimes seen but the prominent cytoplasmic tails and protrusions as seen in this patient are rare. In cases with marked hemophagocytosis, the distinction from reactive hemophagocytosis is crucial and when no clonal marker is present can be difficult. The authors declare no potential conflict of interest.